Modality selective roles of pro-nociceptive spinal 5-HT_2A and 5-HT₃ receptors in normal and neuropathic states

TY - JOUR

T1 - Modality selective roles of pro-nociceptive spinal 5-HT2A and 5-HT3 receptors in normal and neuropathic states

AU - Patel, Ryan

AU - Dickenson, Anthony H.

N1 - Funding Information: This study was funded by the Wellcome Trust Pain Consortium [102645 – Defining pain circuitry in health and disease]. Publisher Copyright: © 2018 The Authors Copyright: Copyright 2018 Elsevier B.V., All rights reserved.

PY - 2018/12

Y1 - 2018/12

N2 - Descending brainstem control of spinal nociceptive processing permits a dynamic and adaptive modulation of ascending sensory information. Chronic pain states are frequently associated with enhanced descending excitatory drive mediated predominantly through serotonergic neurones in the rostral ventromedial medulla. In this study, we examine the roles of spinal 5-HT2A and 5-HT3 receptors in modulating ascending sensory output in normal and neuropathic states. In vivo electrophysiology was performed in anaesthetised spinal nerve ligated (SNL) and sham-operated rats to record from wide dynamic range neurones in the ventral posterolateral thalamus. In sham rats, block of spinal 5-HT3Rs with ondansetron revealed tonic facilitation of noxious punctate mechanical stimulation, whereas blocking 5-HT2ARs with ketanserin had minimal effect on neuronal responses to evoked stimuli. The inhibitory profiles of both drugs were altered in SNL rats; ondansetron additionally inhibited neuronal responses to lower intensity punctate mechanical stimuli and noxious heat evoked responses, whereas ketanserin inhibited innocuous and noxious evaporative cooling evoked responses. Neither drug had any effect on dynamic brush evoked responses nor on spontaneous firing rates in both sham and SNL rats. These data identify novel modality and intensity selective facilitatory roles of spinal 5-HT2A and 5-HT3 receptors on sensory neuronal processing within the spinothalamic-somatosensory cortical pathway.

AB - Descending brainstem control of spinal nociceptive processing permits a dynamic and adaptive modulation of ascending sensory information. Chronic pain states are frequently associated with enhanced descending excitatory drive mediated predominantly through serotonergic neurones in the rostral ventromedial medulla. In this study, we examine the roles of spinal 5-HT2A and 5-HT3 receptors in modulating ascending sensory output in normal and neuropathic states. In vivo electrophysiology was performed in anaesthetised spinal nerve ligated (SNL) and sham-operated rats to record from wide dynamic range neurones in the ventral posterolateral thalamus. In sham rats, block of spinal 5-HT3Rs with ondansetron revealed tonic facilitation of noxious punctate mechanical stimulation, whereas blocking 5-HT2ARs with ketanserin had minimal effect on neuronal responses to evoked stimuli. The inhibitory profiles of both drugs were altered in SNL rats; ondansetron additionally inhibited neuronal responses to lower intensity punctate mechanical stimuli and noxious heat evoked responses, whereas ketanserin inhibited innocuous and noxious evaporative cooling evoked responses. Neither drug had any effect on dynamic brush evoked responses nor on spontaneous firing rates in both sham and SNL rats. These data identify novel modality and intensity selective facilitatory roles of spinal 5-HT2A and 5-HT3 receptors on sensory neuronal processing within the spinothalamic-somatosensory cortical pathway.

KW - 5-HT

KW - Descending facilitation

KW - In vivo electrophysiology

KW - Ketanserin

KW - Neuropathic pain

KW - Ondansetron

KW - Serotonergic pain modulation

KW - Spinal nerve ligation

KW - Ventral posterolateral thalamus

UR - http://www.scopus.com/inward/record.url?scp=85054751231&partnerID=8YFLogxK

U2 - 10.1016/j.neuropharm.2018.09.028

DO - 10.1016/j.neuropharm.2018.09.028

M3 - Article

C2 - 30240783

AN - SCOPUS:85054751231

SN - 0028-3908

VL - 143

SP - 29

EP - 37

JO - Neuropharmacology

JF - Neuropharmacology

ER -